Elastomeric composition containing therapeutic agents and articles manufactured therefrom

ABSTRACT

A novel elastomeric composition of matter comprises a rubber latex and a masterbatch comprising a therapeutic agent in a therapeutically effective amount, a carrier component, titanium dioxide, and clay. A process for the preparation of a novel elastomeric composition of matter containing a therapeutic agent includes the steps of preparing a masterbatch containing a therapeutic agent, adding the masterbatch to a rubber latex and thereafter forming and curing a desired product therefrom. The composition is useful in the manufacture of rubber goods such as surgical and medical products which can be single or multilayered.

TECHNICAL FIELD

This invention relates to elastomeric compositions of matter which haveincorporated therein a therapeutic agent such as an antibiotic compound.The composition also comprises a migratable carrier which continuallyadvances the agent to the surface of the elastomer. The compositions areparticularly suitable for the manufacture of medical and surgicalinstruments such as endo-tracheal tubes, inhalation bags, intravenoustubing, rubber gloves, and specifically, Foley catheters, and can easilybe utilized in conventional multiple-dip manufacturing processes.

Catheters, as well as other medical and surgical instruments, havecustomarily been manufactured from natural latex primarily because theproducts have a low permeability, they are easily fabricated and arerelatively inexpensive. The rubber composition selected must not only besusceptible to sterilization and other cleaning operations, but it mustalso be able to function satisfactorily when in contact with the bodyand its fluids.

BACKGROUND ART

A primary concern in the health care environment is protecting thepatient from infection whether endogenous, exogenous or nosocomial. Oneof the most common causes of hospital acquired infection arises fromcatheterization of the urinary tract. Even though the catheter issterile, protecting the patient from exogenous infection, passagethrough the urethra to the bladder can transfer bacteria to the catheterwhich is then transmitted to the bladder. Other sources include thecollection bag and periurethral area from which bacteria can migratealong the catheter into the bladder.

The problem is particularly prominent in long term catheterizations.Investigations have indicated that the risk of infection increase witheach day of catheterization and that bacteriuria develops in almost 100percent of chronically catheterized patients. In 1982 the Atlanta Centerfor Disease Control reported that approximately one-half millionpatients per year acquire urinary tract infections in acute carehospitals throughout the United States.

No sterile procedure known has been effective against preventinginfections of this type. In an attempt to prevent infections otherwisethe patient can be administered antibiotics systemically andprophylactically. While this provides some help, it is not totallyeffective; moreover, such methods are not without attendant problems.Another preventative step has been to apply antibacterial ointments tothe shaft exterior of the catheter. However, this method provides onlyan initial surface treatment which is substantially removed duringinsertion leaving no protection for the patient with an indwellingcatheter over long period of time.

One relatively recent method of controlling infections attendant the useof catheters is provided in U.S. Pat. No. 4,592,920. This patent isdirected toward a method for producing antimicrobial catheters whichincludes the steps of suspending a comminuted antimicrobial metalcompound in a curable suspending agent and then coating the cathetertherewith. The suspension is then cured to bond it to the surface of thecatheter. While a bonded coating is more permanent than a topicaltreatment with an ointment, it would be more desirable to provide alonger acting treatment by incorporation of the desired compounddirectly into the latex composition, prior to curing.

The mere addition, however, is not satisfactory because the rubber latexcan become destabilized preventing further manufacture or the particularadditive does not remain intact during the manufacturing process orboth. Of course incorporation, if successful, is of no benefit to thepatient unless the desired compound can be brought to the surface of thearticle from within the rubber.

It is known that silicone is a material that can be compounded withrubber latex and will migrate from within the rubber to the surface.U.S. Pat. No. 3,962,519, for instance, provides for mixing siliconecompounds directly into natural and synthetic rubber latex formulationsprior to curing them relies upon the bleeding or migration of thesilicone compound to the external surface of the instrument to provideresistance to unwanted adhesion and water repellency. The patentdiscloses employment of silicone compounds having a molecular weight ofmore than 90,000 and states that the amount present can range from about0.1 to 10% by weight based upon the weight of the rubber. Of course, dueto the migratory behavior of the silicone, the method of this patentdoes not permit relatively high amounts of silicone to be employedwithout causing separation of the silicone from the rubber latex andconcomitant failure of the product.

U.S. Pat. No. 4,242,287 is directed toward an elastomeric compositioncomprising natural rubber latex and a silicone composition present inamounts of more than 10 to about 50 weight per 100 parts of rubber. Thecomposition is stable and allows for continual migration of the siliconeto the surface of the rubber. Articles, such as catheters, that areproduced by multiple dip operations into the latex can be made withoutlater separation of the layers.

Apart from the recognition that silicone could be incorporated intorubber compositions, there has been no incorporation of medication orother therapeutic agents into rubber compositions much less anysuggestion to do so in these patents or within the existing state of theart.

Other rubber implements such as endo-tracheal tubes and rubber glovesmust also be free from bacteria during use to protect exposed areas ofthe patient from bacteria and associated types of infection. Again,sterile procedures and topical antibacterial agents have not providedthe answer.

Moreover, the threat of infectious diseases such as hepatitis, acquiredimmune deficiency syndrome, or AIDS, and the like have made the wearingof rubber gloves by health care workers, other than surgeons, necessaryto protect the wearer. Likewise, condoms have always been proclaimed asan effective means of protecting against the spread of disease. Inaddition to the physical barrier provided by the rubber film, it isdesirable to have incorporated into the foregoing articles varioustherapeutic agents that may be effective against the infectiousmicroorganisms. While no drug has yet been found to be effective againstAIDS, incorporation of such a compound into rubber gloves and condomswould be extremely helpful.

DISCLOSURE OF THE INVENTION

It is therefore an object of the present invention to provide a stableelastomeric composition containers at least a therapeutically effectiveamount of a therapeutic agent.

It is another object of the present invention to provide an elastomericcomposition containing a therapeutic agent medicinal substance thatcontinuously provides that agent at the surface of the elastomer.

It is yet another object of the present invention to provide surgicaland medical instruments, such as Foley catheters and rubber gloves, fromthe elastomeric compositions disclosed herein containing a therapeuticagent.

It is still another object of the present invention to provide a processfor the preparation of an elastomeric composition containing atherapeutic agent that is stable and allows the manufacture of usefulsurgical and medical instruments therefrom via conventional processes.

These and other objects of the present invention, together with theadvantages thereof over the prior art, which shall become apparent fromthe specification that follows, are accomplished by the invention ashereinafter described and claimed.

In general, the preferred elastomeric composition of the presentinvention is prepared by preparing a masterbatch containing atherapeutic agent, adding the masterbatch to an elastomeric formulationwith stirring and thereafter forming and curing a desired producttherefrom. Surgical and medical products can then be formed from thetherapeutic agent-containing elastomeric composition of the presentinvention via conventional processing techniques.

The elastomeric composition generally comprises a rubber latexformulation and from about 7.5 to 30 parts by weight of a masterbatch.The masterbatch includes, based upon the weight of the elastomer, atleast a therapeutically effective amount of a therapeutic agent, atleast about 3 parts by weight of a carrier component, at least about 2.5parts by weight of clay, and at least about 1.5 parts by weight oftitanium dioxide.

PREFERRED EMBODIMENT FOR CARRYING OUT THE INVENTION

Formulation of the elastomeric composition set forth herein generallyincludes the use of a natural rubber latex, a therapeutic agent, and amigratable carrier. Although the examples provided herein disclose theuseof a natural rubber latex having 56.5% total solids content byweight, it is to be understood that other latices as well as syntheticsand mixtures thereof, which have conventionally been employed in themanufacture of rubber surgical and medical instruments, can also beemployed. Acceptable synthetic rubber latices include neoprene,styrene-butadiene rubber or thelike. It should be noted that theaforementioned elastomeric composition may also contain conventionalingredients such as antioxidants, pigments, curing ingredients andstabilizers.

The migratable carrier is preferably employed as one component of atherapeutic masterbatch, discussed more fully hereinbelow. The carriermust have continual migrating capabilities which do not deleteriouslydeform the elastomeric composition. In practice of the presentinvention, the carrier is preferably provided by a silicone compound.Suitable silicone compounds can be selected from polysiloxanes having aviscosity of about 100 centistokes and a viscosity-average molecularweight of about7,000, with dimethylpolysiloxane being exemplary. Oneparticularly satisfactory silicone compound is produced by the SiliconeProducts Department of General Electric, and is identified by the codeSM-2064. This compound is an anionic emulsion having approximately 50%total solidsby weight. It requires a temperature in excess of 260 ° C.to increase its molecular weight and therefore, in curing operations ofthe type conventionally employed in the manufacture of rubber surgicaland medical instruments, it retains its low molecular weight of about7,000.

The amount of the silicone compound added can range from at least 3parts to about 15 parts by weight per hundred parts of rubber (phr).Greater amounts can be tolerated, as disclosed in U.S. Pat. No.4,242,287, the subject matter of which is incorporated herein byreference; however, the higher amounts are not necessary for effectivepractice of the present invention.

In order to control the growth of bacteria in the area surrounding andin communication with articles made from the elastomer, the presentinventionprovides for the addition of antibacterial agents or othertherapeutic agents. A host of antibiotics are known, for instance, whichhave specificactivity against Gram-positive bacteria such as penicillinor Gram-negativebacteria such as streptomycin, or the broad-spectrumantibiotics such as tetracycline. Other specific types includemethicillin, chloramphenicol, aureomycin, terramycin, tetracyn,dimethylchlortetracycline, erythromycin,bacitracin and the like.

It will be appreciated by those skilled in the art that substantiallyany desired antibiotic can be employed. In fact, the present inventioncan provide a variety of rubber products, such as catheters, each with adifferent antibioltic so that the physician can select one that iseffective against a particular bacteria or microorganism. Because of theunique manner in which the antibiotic is incorporated into the rubber,it remains effective despite the manufacturing and curing processes,subsequent storage, use and sterilization.

As other therapeutic agents, a wide variety of compounds may beincluded. Among these are cortisone and other steroids andanti-inflammatory agents;anti-puretic agents; anti-fungal agents;analgesic agents; hormones and essentially any agent or drug that can beabsorbed and utilized transdermally. of course, the antibiotics can beeffective transdermally as well as topically i.e., surface contacteffective. Spermicides may alsobe incorporated into condoms for atopical protection.

The foregoing agents may be added in substantially any therapeuticeffective amount which provides a range of a minimal amount such asabout 0.5 parts by weight per hundred parts of rubber (phr) up to anyamount that does not upset the stability of the latex from which thearticle is to be manufactured. With specific respect to the antibiotics,the amount can be added ranges from about 0.5 to 2.5 phr. Greateramounts are not necessary inasmuch as the material constantly migratesto the surface to provide a therapeutically effective level ofantibiotic. Also, amounts much higher than about 2.5 phr could upset thestability of the latex, resulting in a defective products. Theantibiotic or other therapeutic agent is added via masterbatching aswill be described next.

Masterbatching is a useful technique, described in detail in theaforereferenced U.S. Pat. No. 4,242,287. The masterbatching method wasfirst employed as a means of incorporating large amounts of siliconecompounds without eventual separation from the latex or phasing in thecured elastomer. The masterbatch also contained clay and titaniumdioxide.The clay is added as an aqueous dispersion having about 60%total solids byweight. Kaolin is quite suitable for this purpose and canbe added in a mounts of from about 2.5 to about 8 parts by weight phrwith 4.5 parts being preferred. Titanium dioxide is also added as anaqueous dispersion, having about 50% total solids content, in an amountof from about 1.5 to about 7 parts phr with 1.5 being preferred. Thesilicone carrier is then added in an amount of from about 3 to 15 partswith 6 being preferred.

As described in the aforementioned patent, the titanium dioxide andkaolin dispersions are combined with high speed stirring followed by theadditionof the silicone emulsion at lower speeds for approximately 10minutes. It has now been found according to the method of the presentinvention that dispersing the therapeutic agent in the masterbatch ofthe carrier and other additives is a novel and effective manner ofincorporating the former into the elastomer. When added viamasterbatching, the therapeutic agent is protected from any reactionwith the latex as would be deleterious to the former or as woulddestabilize the latex. After the addition of the masterbatch to thelatex and subsequent curing, the therapeutic agent is stablyincorporated in the elastomeric product. The homogeneity of themasterbatch compound provides a slow and continual migration of thesilicone, as such the therapeutic agent is freely carriedto the surfaceof the elastomeric product in a continual manner an in an effectiveamount.

The masterbatch of the present invention is formed essentially asdescribedhereinabove, as well as in U.S. Pat. No. 4,242,287, except forthe additionof the step wherein the therapeutic agent is added to anddispersed within the other masterbatch elements. The therapeutic agentis added in the formof a dispersion to the masterbatch with slowagitation over a period of about 12 hours. Afterwards, the masterbatchis added slowly to the rubber latex at low stirring speeds, as describedin the aforementioned U.S. Pat.No. 4,242,287. Depending on the amount ofthe therapeutic agent that is added, the total amount of masterbatchadded will equal from about 7 to 30parts phr which includes thetherapeutically effective amount of agent, e.g., 0.5 to 2.5 phr in thecase of antibiotics and at least 0.5 phr of other agents.

In order to demonstrate the effectiveness of the present invention, amasterbatch was prepared with and without an antibiotic, Neomyacin, asthetherapeutic agent and each was added to a rubber latex formulation.The composition of the masterbatch and rubber latex compositions arepresentedin Tables I and II, respectively. Parts are given per 100 partsof rubber by weight.

                  TABLE I                                                         ______________________________________                                        Neomyacin Masterbatch                                                                   Control                                                                              Ex. 1.sup.a                                                                             Ex. 2.sup.b                                                                           Ex. 3                                      ______________________________________                                        Neomyacin   0        1.5       1.5   2.5                                      TiO.sub.2   2.5      2.5       2.5   2.5                                      Clay        7.5      7.5       7.5   7.5                                      G.E. Silicon                                                                              10.0     10.0      10.0  10.0                                     SM-2064                                                                       ______________________________________                                         .sup.a Neomyacin added to catheter balloon only                               .sup.b Neomyacin added to entire catheter composition                    

                  TABLE II                                                        ______________________________________                                        Rubber Latex                                                                                   Percent                                                                       Total          Dry Wt.                                                                              Wet Wt.                                Component                                                                             Parts    Solids   C.F.  (gms)  (gms)                                  ______________________________________                                        Rubber  100.0    56.5%    1.027 1998.13                                                                              3632.0                                 latex.sup.a                                                                   Zetax.sup.b                                                                           0.2      25.0%          5.99   24.0                                   Methyl  0.3      35.0           5.99   17.1                                   tuads.sup.c                                                                   ZnO     0.4      50.0%          7.99   16.0                                   ______________________________________                                         .sup.a Natural rubber latex, contains 0.7 parts sulfur                        .sup.b Registered trademark of Goodyear Tire and Rubber Company for           zinc2-mercaptobenzothiazole                                                   .sup.c Registered trademark of R. T. Vanderbilt Co., Inc. for                 tetramethylthiuram disulfide                                             

The masterbatch was prepared first and then added to the latex withstirring for 30 minutes. Test panels of elastomer were prepared bycoagulant dipping and cured for 30 minutes at 70 ° C.

In order to demonstrate the effectiveness of the incorporatedantibiotic, sections from the two panels were tested against theorganism Staphylococcus aureus. To do so, a turbid suspension of thetest organism was first prepared. A lawn of the test organism wasapplied to individual tryptic soy agar plates 15×100 mm, using sterileswabs and rotary plater. Test samples of the Control and Example Nos. 1to 3 were placed inthe center of the duplicate test plates and theplates were then incubated for a minimum of 48 hours, or until a lawn oftest organisms appeared. Following incubation, zones of inhibition weremeasured and the zones reported in millimeters. Zones were measured fromthe edge of the sample to the edge of the bacterial lawn and have beenreported in Table III.

                  TABLE III                                                       ______________________________________                                        Zones of Inhibition                                                                               Effect of Neomyacin Incorporation                         Test No.                                                                              Example No. Into Natural Rubber Latex                                 ______________________________________                                        1       1           5.5                                                               2           8.5                                                               Control     4.5                                                       2       3           3.0                                                               Control     1.0                                                       ______________________________________                                    

The effect of the Neomyacin incorporation into Examples No. 1 to 3 isdemonstrated by the extended zones of inhibition compared to the Controlsamples. In Test No. 1, Neomyacin at 1.5 phr was added to the balloondipping composition for Ex. No. 1 and the catheter composition for Ex.No.2, and was found to be more effective in the latter instance. In TestNo. 2, Neomyacin at 2.5 phr was added to the catheter composition forEx. No. 3.

Thus it can be seen that by employing the process disclosed herein, itis possible to prepare a novel elastomer having a therapeuticallyeffective amount of a therapeutic agent which remains homogeneouslydistributed throughout the rubber latex even after vulcanization. Aswill be apparent to those skilled in the art, the composition of thenovel elastomer disclosed herein can be selected according toavailability of ingredients and nature of the end product. The methodsgenerally available for making known surgical and medical instrumentscan be practiced with the elastomeric composition disclosed herein whichin turn can enable the worker to achieve the objects of the invention.

It should likewise be apparent that with the ability to incorporatetherapeutic agents into natural and synthetic rubber latices, a varietyofrubber articles can be manufactured that can be used to treat and/orprotect the wearer or user as well as those with whom he or she makescontact.

It is therefore, believed that the penetration and use of the elastomersdisclosed herein can be determined without departing from the spirit ofthe invention herein disclosed and described, the scope of the inventionbeing limited solely by the scope of the attached claims.

I claim:
 1. A homogeneous elastomeric composition of matter comprising:a rubber latex, said rubber being selected from the group consisting of natural rubber, synthetic rubber and mixtures thereof; and from about 7.5 to about 30 parts by weight, based upon the weight of 100 parts of said rubber, of a masterbatch comprising:a therapeutically effective amount of a therapeutic agent; at least about 3 parts by weight, per 100 parts of rubber, of a carrier component selected from the group consisting of polysiloxane emulsions; at least about 2.5 parts by weight, per 100 parts of rubber, of clay; and at least about 1.5 parts by weight, per 100 parts of rubber, of titanium dioxide.
 2. A composition of matter, as set forth in claim 1, wherein said therapeutic agent is selected from the group consisting of antibiotics, anti-inflammatory agents, anti-puretic agents, anti-fungal agents, analgesic agents and spermicides.
 3. A composition of matter, as set forth in claim 2, wherein said therapeutic agent is an antibiotic.
 4. A composition of matter, as set forth in claim 3, wherein said therapeutically effective amount of said antibiotic is from about 0.5 to 2.5 parts by weight, per 100 parts of rubber.
 5. A composition of matter, as set forth in claim 4, wherein said antibiotic is Neomyacin.
 6. A composition of matter, as set forth in claim 5, wherein said rubber latex is natural rubber.
 7. A homogeneous elastomeric composition of matter comprising:a rubber latex, said rubber being selected from the group consisting of natural rubber, synthetic rubber and mixtures thereof; and from about 7.5 to about 30 parts by weight, based upon the weight of 100 parts of said rubber, of a masterbatch comprising:a therapeutically effective amount of a therapeutic agent, selected from the group consisting of anti-inflammatory agents, anti-puretic agents, anti-fungal agents, analgesic agents and spermicides; at least about 3 parts by weight, per 100 parts of rubber, of a carrier component selected from the group consisting of polysiloxane emulsions; at least about 2.5 parts by weight, per 100 parts of rubber, of clay; and at least about 1.5 parts by weight, per 100 parts of rubber, of titanium dioxide.
 8. A composition of matter, as set forth in claim 7, wherein said rubber latex is natural rubber. 